A Phase 1I/II, Open-label Study of Oral S241656 (BDTX-4933) as Monotherapy and in Combination With Other Anti-Cancer Therapies in Patients With KRAS, BRAF and Other Selected RAS/MAPK Mutation-Positive Malignancies

Study Identifier:
BDTX-4933-101
CT.gov Identifier:
NCT05786924
EudraCT Identifier:
202552347416
EU Trial (CTIS) Number:
2025-523474-16-00
Study Contact Information:
N/A
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Study Summary

BDTX-4933-101 is a first-in-human, open-label, Phase 1/2 dose escalation, dose optimization and expansion study designed to evaluate the safety and tolerability of S241656 as monotherapy and in combination with other anti-cancer therapies in participants with selected advanced malignancies. The study population for the Dose Escalation part of the study comprises adults with recurrent advanced/metastatic non-small cell lung cancer (NSCLC), Gastrointestinal (GI) cancers, and other solid tumors harboring KRAS, HRAS, NRAS, BRAF, and/or CRAF (Rapidly Accelerated Fibrosarcoma (RAF1)) mutations or alterations. A dose optimization part in adults with NSCLC may follow the dose escalation phase if the sponsor, in consultation with the safety review committee, decides it is necessary to further characterize the optimal dose. However, the study may also proceed directly to the expansion phase. The study population for the Dose Expansion part of the study comprises adults with advanced/metastatic NSCLC with KRAS and/or BRAF mutations, and with Pancreatic Ductal AdenoCarcinoma (PDAC), ColoRectal Cancer (CRC), and Biliary Tract Cancer (BTC) with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations and alterations. All patients will self-administer S241656 orally in 28-day cycles until disease progression, toxicity, withdrawal of consent, or termination of the study. To evaluate safety and tolerability, the preliminary recommended Phase 2 dose, and antitumor activity of BDTX-4933 in adults with recurrent advanced/metastatic cancers harboring BRAF, CRAF, or NRAS mutations.

Dose Escalation: To evaluate the safety and tolerability of S241656 in the different indications and cumulatively when administered as monotherapy and in combination Dose Expansion: To evaluate the antitumor activity of S241656 when administered as a monotherapy and in combination

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Non-Small Cell Lung Cancer
Hematological Cancer
Unspecified Cancer
Gene Mutations
Metastatic Lung Cancer
Recurrent Lung Cancer
Solid Tumor
Solid Carcinoma
Thyroid
Bowel (Colorectal)
Histiocytic and Dendritic Cell Neoplasm
Brain
Biomarkers
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Female & Male
Age
18+ years
Study Drug
Drug: Experimental: Part 1A: Dose Escalation NSCLC
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Drug: Other Names:
Drug: Drug: Nab-paclitaxel
Drug: Experimental: Part 1D: Dose Escalation CRC
Drug: Drug: FOLFIRI
Drug: Drug: Cetuximab
Drug: Drug: Panitumumab
Drug: Experimental: Part 1E: Dose Escalation Other Solid Tumors
Drug: Experimental: Part 2A: Dose Optimization NSCLC
Drug: Experimental: Part 2A1: Dose Expansion NSCLC with KRAS non-G12C mutations
Drug: Experimental: Part 2A2: Dose Expansion NSCLC with BRAF mutations
Drug: Experimental: Part 2A3: Dose Expansion NSCLC with KRAS non-G12C or BRAF mutations/alterations
Drug: Experimental: Part 2A4: Dose Expansion NSCLC with a KRAS G12C mutation
Drug: Experimental: Part 2B1: Dose Expansion PDAC
Drug: Experimental: Part 2B2: Dose Expansion CRC
Drug: Experimental: Part 2B3: Dose Expansion BTC
Drug: Experimental: Part 2C1: Dose Expansion PDAC
Drug: Experimental: Part 2D1: Dose Expansion CRC
Drug: Experimental: Part 2F: Exploratory Food Effect
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting

Requirements information
Inclusion criteria
  • Life expectancy of ≥ 12 weeks in the opinion of the investigator.
  • Histologically or cytologically confirmed recurrent locally advanced (unresectable) or metastatic solid tumors with documented RAS or RAF mutations or alterations.
  • Adequate bone marrow and organ function.
  • Recovered from toxicity to prior anti-cancer therapy.
  • Part 1 Dose Escalation cohort ONLY:
  • Part 1A: Advanced/metastatic NSCLC with KRAS non-G12C, HRAS, NRAS, BRAF or CRAF (RAF1) mutations or alterations
  • Part 1B: Advanced/metastatic GI tumors (e.g., PDAC, CRC, and BTC) with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations
  • Part 1C: Advanced/metastatic PDAC with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations
  • Part 1D: Colorectal adenocarcinoma with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations
  • Part 1E: Other advanced/metastatic non-GI, non-NSCLC solid tumors with KRAS, HRAS, NRAS, BRAF, CRAF (RAF1) mutations or alterations
  • Part 2 Dose Optimization and Expansion cohorts ONLY:
  • Part 2A: Advanced/metastatic NSCLC with KRAS non-G12C mutations and/or BRAF mutations
  • Part 2A1: Advanced/metastatic NSCLC with KRAS non-G12C mutations
  • Part 2A2: Advanced/metastatic NSCLC with BRAF mutations
  • Part 2A3: Advanced/metastatic NSCLC with KRAS non-G12C or BRAF mutations or alterations and active CNS metastatic disease
  • Part 2A4: Advanced/metastatic NSCLC with a KRAS G12C mutation
  • Part 2B1: Advanced/metastatic PDAC with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations
  • Part 2B2: Advanced/metastatic CRC with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations
  • Part 2B3: Advanced/metastatic BTC (adenocarcinoma) with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations - Life expectancy of => 12 weeks in the opinion of the investigator.
  • - Histologically or cytologically confirmed recurrent locally advanced (unresectable) or metastatic solid tumors with documented RAS or RAF mutations or alterations.
  • - Adequate bone marrow and organ function.
  • - Recovered from toxicity to prior anti-cancer therapy.
  • Part 1 Dose Escalation cohort ONLY:
  • - Part 1A: Advanced/metastatic NSCLC with KRAS non-G12C, HRAS, NRAS, BRAF or CRAF (RAF1) mutations or alterations
  • - Part 1B: Advanced/metastatic GI tumors (e.g., PDAC, CRC, and BTC) with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations
  • - Part 1C: Advanced/metastatic PDAC with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations
  • - Part 1D: Colorectal adenocarcinoma with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations
  • - Part 1E: Other advanced/metastatic non-GI, non-NSCLC solid tumors with KRAS, HRAS, NRAS, BRAF, CRAF (RAF1) mutations or alterations
  • Part 2 Dose Optimization and Expansion cohorts ONLY:
  • - Part 2A: Advanced/metastatic NSCLC with KRAS non-G12C mutations and/or BRAF mutations
  • - Part 2A1: Advanced/metastatic NSCLC with KRAS non-G12C mutations
  • - Part 2A2: Advanced/metastatic NSCLC with BRAF mutations
  • - Part 2A3: Advanced/metastatic NSCLC with KRAS non-G12C or BRAF mutations or alterations and active CNS metastatic disease
  • - Part 2A4: Advanced/metastatic NSCLC with a KRAS G12C mutation
  • - Part 2B1: Advanced/metastatic PDAC with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations
  • - Part 2B2: Advanced/metastatic CRC with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations
  • - Part 2B3: Advanced/metastatic BTC (adenocarcinoma) with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations When providing informed consent, the Age must be 18 years of age or older, or an adult as permitted by applicable local laws.
  • Researchers believe that life expectancy is ≥ 12 weeks.
  • Disease Criteria: a. Histologically or cytologically confirmed recurrent locally advanced (unresectable) or metastatic solid tumors with a documented RAS or RAF mutation or alteration prior to screening by a validated molecular diagnostic test (e.g., next-generation sequencing [NGS]), including IVD or laboratory-built-in test (LDT), as follows: b. Part 1A: i. Part 1A (NSCLC dose-escalation): Advanced/metastatic NSCLC with a documented KRAS (non-G12C), HRAS, NRAS, BRAF, or CRAF (RAF1) mutation or alteration, and having received at least one prior line of systemic therapy. v. Part 1B: (GI tumor dose-escalation) Advanced/metastatic GI tumors (e.g., PDAC, CRC, and BTC) with a documented KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutation or alteration, unsuitable for surgical resection, and having received at least one prior line of systemic therapy, and refusing or not meeting any available standard treatment criteria. vii. Part 1C (Dose-escalating combination therapy for PDAC): Advanced/metastatic PDAC with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations, unsuitable for surgical resection, having received prior first-line systemic therapy, and suitable (at the investigator's judgment) for second-line therapy with gemcitabine and albumin-bound paclitaxel. viii. Part 1D (Dose-escalating combination therapy for CRC): Colorectal cancer with KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutations or alterations, unsuitable for surgical resection, having received prior first-line systemic therapy, and suitable (at the investigator's judgment) for second-line therapy with FOLFOX6/FOLFOX7 or FOLFIRI in combination with cetuximab or panitumumab. vi. Part 1E (Dose escalation for other solid tumors): Other advanced/metastatic non-GI, non-NSCLC solid tumors with previously documented KRAS, HRAS, NRAS, BRAF, CRAF (RAF1) mutations or alterations, after discussion with the sponsor, and who have received at least one first-line prior systemic therapy.
  • Disease Criteria: c. Part 2: i. Part 2A (Monotherapy Dosage Optimization): Participants with advanced/metastatic NSCLC carrying KRAS (non-G12C) mutations and/or BRAF mutations who have received one or more lines of prior systemic therapy. Eligible prior therapy includes: platinum-based chemotherapy alone, checkpoint inhibitors alone, or platinum-based therapy combined with an immune checkpoint inhibitor. ii. Part 2A1 (NSCLC KRAS (non-G12C) Dosage Extension): Participants with advanced/metastatic NSCLC carrying KRAS (non-G12C) mutations. Participants must have received up to two lines of prior standard systemic therapy (adjuvant and maintenance therapy are not included in this limit). Eligible prior therapy includes: platinum-based chemotherapy alone, checkpoint inhibitors alone, or platinum-based therapy combined with an immune checkpoint inhibitor. iii. Part 2A2 (NSCLC BRAF Dosage Extension): Participants with advanced/metastatic NSCLC carrying BRAF mutations. Participants must have received up to two lines of prior standard systemic therapy (adjuvant and maintenance therapy are excluded from this limit). Eligible prior therapy includes platinum-based chemotherapy with or without checkpoint inhibitors, and targeted therapy against BRAF mutations. Eligible participants with BRAF V600E mutations must have received approved BRAF targeted therapy. iv. Part 2A3 (NSCLC Active Brain Metastases Dosage Extension): Participants with advanced/metastatic NSCLC carrying KRAS (non-G12C) or BRAF mutations or alterations and active CNS metastatic disease are defined as those who have not received CNS-targeted therapy since the beginning of their careers and have no clinically symptomatic significant or progressive neurological symptoms and/or require high doses (8 mg/daydexamethasone or equivalent) and/or increased steroid doses for new or progressive brain metastases. v. Part 2A4 (NSCLC KRAS G12C Dosage Extension): Participants with advanced/metastatic NSCLC carrying a KRAS G12C mutation who have received G12C targeted therapy and experienced disease progression. Note: Participants with stable CNS metastases are eligible for Parts 2A1, 2A2, and 2A4. vi. Part 2B1 (PDAC Monotherapy Dosage Extension): Participants with advanced/metastatic PDAC with a documented KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutation or alteration who are unsuitable for surgical resection, have received at least one prior line of systemic therapy, and refuse or do not meet any available standard of care.
  • Disease Criteria: vii. Part 2B2 (CRC Monotherapy Dosage Extension): Participants with advanced/metastatic CRC who have a documented KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutation or alteration, are unsuitable for surgical resection, have received at least one prior line of systemic therapy, and refuse or do not meet any available standard of care. viii. Part 2B3 (BTC Monotherapy Dosage Extension): Participants with advanced/metastatic BTC (adenocarcinoma) who have a documented KRAS, HRAS, NRAS, BRAF, and/or CRAF (RAF1) mutation or alteration, are unsuitable for surgical resection, have received at least one prior line of systemic therapy, and refuse or do not meet any available standard of care. ix. Part 2F (Exploratory Food Effects): Participants with any advanced/metastatic tumor type who carry a KRAS (non-G12C) and/or BRAF mutation or alteration, have received at least one prior line of systemic therapy, and agree to participate in the food effects sub-study.
  • Tumor tissue test results required to document the mutations needed for eligibility must be provided during the screening process. If possible, the tumor tissue sample should be sent to the sponsor.
  • The disease must be measurable by RECIST 1.1. Note: Participants must have a confirmed mutation as defined in the Inclusion criteria of the relevant study section/group, which must have been determined prior to screening using an empirical molecular diagnostic test (e.g., next-generation sequencing) performed in a laboratory certified or accredited according to local or regional regulatory standards (e.g., CLIA, CAP, ISO 15189). Approved IVD tests or validated LDT tests may be included, to the extent permitted by local regulations.
  • An ECOG fitness level of 0 or 1 (or 2 after review by the sponsor may also qualify) is acceptable.
  • The following laboratory assessments performed prior to the first administration of the study drug indicate adequate organ function and bone marrow reserve: a. Bone marrow function: Absolute neutrophil count (ANC) ≥ 1000/μL; platelet count > 100,000/μL; hemoglobin ≥ 8.5 g/dL. b. Renal function: Creatinine clearance ≥ 60 mL/min as estimated by the Cockcroft-Gault formula, or serum creatinine within the normal limits according to institutional guidelines. c. Liver function: Total bilirubin ≤ 1.5 × Upper Limit of Normal (ULN), unless there is evidence of Gilbert's syndrome, in which case total bilirubin ≤ 3.0 × ULN; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN (≤ 5.0 × ULN if liver metastases are present). d. Coagulation Studies: Prothrombin time (PT-INR) and apoptosis kinase time (aPTT), corrected for international normalized ratio (UNR), ≤ 1.5 × ULN. Participants who have received a stable, maintenance anticoagulation regimen for at least 30 days prior to study drug administration may have a PT-INR > 1.5 × ULN if the investigator deems them suitable for the study. Sufficient justification must be provided to the sponsor before enrollment.
  • All clinically relevant toxicities associated with prior treatment must have recovered to grade 1 or baseline levels (except for alopecia, lymphopenia, hypothyroidism, or grade 2 neuropathy adequately controlled by stabilizing agents).
  • Participants who have undergone surgical removal of tumors must have fully recovered from the surgery and have assessable or measurable residual lesions.
  • Contraceptive criteria: a. Women of childbearing potential (WOCBP) must agree to use a highly effective method of contraception during the study treatment period and for 5 half-lives plus 6 months after the last dose of the study drug. If using oral contraceptives, women should have been consistently using the same contraceptive (i.e., the same active ingredient) for at least 3 months prior to the first dose of IMP. b. Male participants must agree to use condoms during intercourse throughout the study treatment period and for 5 half-lives plus 90 days after the last dose of the study drug. Contraception for their female partners should also be considered. For male participants receiving gemcitabine, this period is extended to 6 months. c. Contraception is not applicable if the participant is sterilized, has undergone vasectomy or hysterectomy, or abstains from sexual activity. d. Egg donation is not permitted during the study period and for at least 5 half-lives plus 6 months after the last dose of the study drug. e. Sperm donation is not permitted during the study period and for at least 5 half-lives plus 90 days after the last dose of the study drug. For male participants receiving gemcitabine, this period is extended to 6 months.
  • Provide written informed consent and be willing and able to comply with the requirements of the research protocol, including swallowing the study drug.
  • Participants with stable central nervous system (CNS) metastases are eligible if they meet all of the following criteria (Note: This does not apply to participants in Part 2A3—for the definition and Inclusion criteria for “active brain metastases,” see IC#3(c)(iv)): a. Completion of prior CNS-targeted therapy: Surgical resection and/or stereotactic radiosurgery must have been completed ≥ 14 days prior to the first dose of the study drug. Whole-brain radiotherapy must have been completed ≥ 28 days prior to the first dose of the study drug. b. Radiographic stability: Pre-treatment imaging obtained within 28 days prior to the first dose should show no new or enlarged lesions and no evidence of progression relative to previous scans. Any residual lesions must be clearly non-progressive. c. Neurological stability: No new or worsening neurological signs/symptoms attributable to CNS disease within 14 days prior to the first dose. No poorly controlled seizures (defined as any seizure activity within 14 days despite the use of ≥ 2 anticonvulsants). d. Corticosteroid requirements: Participants must have discontinued systemic corticosteroids or be receiving a stable or tapering dose of ≤ 10 mg prednisone equivalent/day (or ≤ 2 mg dexamethasone/day) for ≥ 7 days (before the first dose). e. Anticonvulsant requirements: If anticonvulsants are used for seizure prophylaxis or control, the regimen must be stable or tapering for ≥ 7 days before the first dose. Use of enzyme-inducing antiepileptic drugs is discouraged; if unavoidable, a medical monitor must be consulted.
  • Exclusion Criteria:
Exclusion criteria
  • Key Exclusion Criteria:
  • Cancer that has a known MEK1/2 mutation.
  • Known allergy/hypersensitivity to excipients of S241656 or to any of the registered IMPs administered in combination.
  • Any contra-indication, to use of any of the combination chemotherapy or anti-EGFR therapy partners administered as part of this trial.
  • Major surgery within 4 weeks of study entry or planned during study.
  • Ongoing anticancer therapy.
  • Ongoing radiation therapy.
  • Uncontrolled or active clinically relevant bacterial, fungal, or specific viral infection requiring systemic therapy.
  • Clinically significant cardiovascular disease.
  • Symptomatic spinal cord compression.
  • Evidence of active malignancy (other than study-specific malignancies) requiring systemic therapy within the next 2 years.
  • History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO.
  • Females who are pregnant or breastfeeding.
  • Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.
  • Prior use of experimental agents that target the KRAS/BRAF/MEK/ERK pathway. - Cancer that has a known MEK1/2 mutation.
  • - Known allergy/hypersensitivity to excipients of S241656 or to any of the registered IMPs administered in combination.
  • - Any contra-indication, to use of any of the combination chemotherapy or anti-EGFR therapy partners administered as part of this trial.
  • - Major surgery within 4 weeks of study entry or planned during study.
  • - Ongoing anticancer therapy.
  • - Ongoing radiation therapy.
  • - Uncontrolled or active clinically relevant bacterial, fungal, or specific viral infection requiring systemic therapy.
  • - Clinically significant cardiovascular disease.
  • - Symptomatic spinal cord compression.
  • - Evidence of active malignancy (other than study-specific malignancies) requiring systemic therapy within the next 2 years.
  • - History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO.
  • - Females who are pregnant or breastfeeding.
  • - Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.
  • - Prior use of experimental agents that target the KRAS/BRAF/MEK/ERK pathway. Cancers with known MEK1/2 mutations.
  • According to the label and local guidelines, there is a known history of hypersensitivity/allergic reaction to the excipients of S241656 or any of the registered IMPs used in combination with it.
  • Those who have undergone major surgery within 4 weeks prior to study enrollment or plan to undergo major surgery during the study period are permitted to undergo minor surgical procedures (e.g., port-a-catheter implantation, uncomplicated central venous catheterization, or fine-needle aspiration), but sufficient time must be allowed for wound healing (based on clinical judgment).
  • Those who were receiving or had recently received anticancer therapy within the following timeframes prior to their first dose of the investigational drug: a. Non-chemotherapy/non-immunotherapy anticancer drugs < 28 days or < 5 half-lives, whichever is shorter. b. Chemotherapy < 21 days. c. Immunotherapy or cell therapy < 28 days.
  • If you have been receiving or recently received radiation therapy within the following timeframes prior to your first dose of the investigational drug: a. Radiation therapy (excluding palliative radiation therapy for bone pain relief) < 14 days. b. Palliative radiation therapy for bone pain relief < 48 hours. c. Stereotactic or small field brain radiation < 7 days. d. Whole brain radiation < 14 days.
  • Clinically relevant bacterial or fungal infections that are poorly controlled and require systemic treatment.
  • Known human immunodeficiency virus (HIV) infection is excluded unless the following criteria are met: a. CD4+ T cell (CD4+) count > 350 cells/μL at screening, and b. no opportunistic infection as defined by acquired immunodeficiency syndrome (AIDS) within the 12 months prior to screening, and c. antiretroviral therapy has been received for ≥ 28 days and/or viral load < 400 copies/mL at screening (or undetectable according to local institutional standards).
  • Participants must have a history of active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection, or be known to have active HBV or active hepatitis C virus (HCV) infection. Note 1: Participants who have completed curative HBV or HCV treatment and whose HBV or HCV viral load is below quantitative levels should not be excluded. Note 2: Participants with chronic HBV or HCV infection must be receiving adequate antiretroviral therapy, or their HBV or HCV must be well controlled, as evidenced by a HBV or HCV viral load below quantitative levels.
  • Clinically significant cardiovascular conditions include: a. Within 6 months prior to enrollment: cerebrovascular accident/stroke; myocardial infarction; unstable angina; poorly controlled atrial fibrillation of any grade. b. History of congestive heart failure (New York Heart Association class ≥ II); second- or third-degree atrioventricular block (unless paced) or any atrioventricular block with a PR interval lasting > 220 msec; or persistent arrhythmia with NCI CTCAE ≥ 2. c. Fridericia-corrected QT interval (QTcF) lasting > 470 msec (≥ 2 independent ECG readings, triplicate each). d. History of long QT syndrome or torsades de pointes.
  • Progressive CNS metastases (not applicable to participants in Part 2A3) or primary CNS tumors: a. Regarding progressive CNS metastases (i.e., symptomatic brain metastases): Participants with progressive neurological symptoms or requiring increased corticosteroid doses to control CNS disease are excluded from the trial. If a participant requires corticosteroids to manage CNS disease, the dose must be stable for two weeks prior to Day 1 of Cycle 1. (Note: Participants with CNS gliomas are excluded from the study.) b. Primary CNS tumors are excluded as another type of active malignancy.
  • Symptomatic spinal cord compression.
  • Researchers believe that moderate to severe cognitive impairment or mental disorders can affect participants' ability to comply with research requirements.
  • Evidence of active malignant tumors requiring systemic treatment within the next 2 years (excluding malignant tumors specifically defined in this study). a. Exceptions: Non-melanoma skin cancer, melanoma in situ, cervical carcinoma in situ, papillary thyroid carcinoma, ductal carcinoma in situ of the breast, superficial bladder cancer, or ablated/resected kidney tumors ≤ 4 cm, or localized and presumed cured prostate cancer. b. Participants receiving long-term anti-hormonal therapy for a previous malignant tumor are permitted enrollment provided that the malignant tumor has not been active within the past 2 years. c. Participants with other early-stage malignant tumors whose potential risk to the study is low or does not interfere with the interpretation of study results may be considered for inclusion, subject to consideration by the investigator and prior approval from the sponsor.
  • Concomitant use of prohibited medications (Concomitant Medication Guidelines). In addition to proton pump inhibitors (PPIs) (including potassium-competitive acid blockers), participants must discontinue any medications, herbal supplements, and foods that are potent or moderate inhibitors of cytochrome P450 (CYP) 3A4 at least 7 days prior to Day 1 of Cycle 1. The same guidelines apply to potent or moderate inducers, but they must be discontinued at least 14 days prior to Day 1 of Cycle 1.
  • As determined by the researchers and the sponsor, the study drug was found to be malabsorbed due to a history of gastrointestinal surgery, delayed gastric emptying, ulcerative colitis or Crohn's disease (requiring steroid therapy), refractory nausea and vomiting, or other conditions that may affect the oral absorption, distribution, metabolism, or excretion of the study drug.
  • A history of retinal vein occlusion (RVO) or current evidence of it, or current RVO risk factors (e.g., poorly controlled glaucoma or high intraocular pressure, hyperviscosity syndrome or hypercoagulable syndrome).
  • Pregnant or breastfeeding women. For WOCBP screening, a negative serum pregnancy test is required, and a negative urine test must be performed before the first dose of the study drug.
  • They are actively receiving systemic treatment or direct medical intervention in another therapeutic clinical study.
  • Any reason that the investigator or sponsor believes would prevent a participant from completing the first 28-day treatment cycle (DLT phase), or any medical condition or laboratory abnormality that would increase the risk associated with participation in the study or interfere with the interpretation of study results.
  • Previous use of investigational drugs or other research drugs targeting the KRAS/BRAF/MEK/ERK pathways, and the investigator or sponsor believes that this may interfere with the interpretation of the research results.
  • 20
  • :
  • twenty one Participants must have experienced a grade ≥ 3 serious adverse event with a BRAF inhibitor, and the investigator believes this may put the participant at risk of relapse. (Note: Participants may qualify after discussion with a medical monitor.)
  • 21
  • :
  • twenty two There are no contraindications to any combination chemotherapy or anti-EGFR therapy companion drugs administered as part of this trial.

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START San Antonio
San Antonio, TX, United States, 78229
Investigator
Amita Patnaik
Status
Recruiting
Condition(s) Treated at Site
Non-Small Cell Lung Cancer
Hematological Cancer
Unspecified Cancer
Gene Mutations
Metastatic Lung Cancer
Recurrent Lung Cancer
Solid Tumor
Solid Carcinoma
Thyroid
Bowel (Colorectal)
Histiocytic and Dendritic Cell Neoplasm
Brain
Biomarkers
Location
START Midwest
Grand Rapids, MI, United States, 49546
Investigator
Manish Sharma
Status
Recruiting
Condition(s) Treated at Site
Non-Small Cell Lung Cancer
Hematological Cancer
Unspecified Cancer
Gene Mutations
Metastatic Lung Cancer
Recurrent Lung Cancer
Solid Tumor
Solid Carcinoma
Thyroid
Bowel (Colorectal)
Histiocytic and Dendritic Cell Neoplasm
Brain
Biomarkers